1. Field of the Invention
The present invention relates to a process for inhibiting deoxyribonucleotide triphosphate biosynthesis by cells, in particular animal, human or plant cells.
2. The Prior Art
It is known that genetic information is carried by the deoxyribonucleic acid (DNA) present in the cell nucleus. DNA comprises a double helix composed of nucleotides, which is fundamental to living organisms, whether animals or plants.
As is known, nucleotides are formed from a sugar, a heterocyclic nitrogenous base and at least one phosphate group. Four phosphates are present in the nucleotides which constitute DNA: deoxyguanidine triphosphate (dGTP), deoxythymidine trisphosphate (dTTP), deoxyadenosine triphosphate (DATP) and deoxycytidine triphosphate (dCTP).
It was noted some years ago that cancerous cells, because they are dividing rapidly, consume a large quantity of nucleotide triphosphates. Research has consequently focused on medicines capable of inhibiting the formation of the deoxyribonucleotides, such as for example 5-fluorouracil, aminopterin and amethopterin (c.f. J. David Rawn, Biochemistry, page 648). Hydroxyurea may also be mentioned, which non-selectively inhibits ribonucleotide reductase, and consequently all the nucleotides involved in DNA synthesis (c.f. "DRUG, Facts and comparisons", J.B. Lippincott Company, 1990, pages 2258 and 2259; P. Reichard, "From RNA to DNA, why so many ribonucleotide reductases?", Science, volume 260, 1993, pages 1773-1776).
The disadvantage of these products is that, given their lack of selectivity, they inhibit mechanisms which are indispensable to healthy, non-cancerous cells and relate to deoxynucleotides, such as for example intracellular energy transport and the enzymatic reactions catalyzed thereby. Treatment with these products consequently entails considerable toxicity for all cells.
The effect of an analogue of dCTP, cytosine arabinoside or cytarabine, which acts by taking the place of the natural molecule in cellular DNA by means of a competitive phenomenon has already been investigated (c.f. "DRUG" op. cit., pages 2192-2196). This product is not active when taken orally and must be administered with great caution.
Fundamental studies have moreover been undertaken to attempt to combine hydroxyurea with cytarabine. The expected effect was to replace with cytarabine the quantity of dCTP reduced by the action of hydroxyurea (c.f. abstract supplied by the database Medline Express of Schilsky, R. L. et al. "Laboratory and clinical studies of biochemical modulation by hydroxyurea", Semin. Onc. Jun. 19, 1992 (3, suppl. 9), 84-89).
Cell lines other than those which are cancerous may have a greatly elevated proliferation rate. Such is the case for lymphocyte cells and the smooth muscle cells of blood vessels during organ transplants (allografts).
Attempts have already been made to control these cells by restricting their level of deoxynucleotides. Mycophenolic acid (MPA) or one of the derivatives thereof which blocks inosine monophosphate dehydrogenase, so bringing about a reduction in intracellular dGTP and consequently blocking DNA synthesis by these cells may be mentioned by way of example (c.f. Pichimayr, R., "Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection", The Lancet, volume 345, May 27, 1995, pages 1321-1325; Sollinger, H. W., "Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients", Transplantation, volume 60, 225-232, number 3, 1995; Gregory, C. R., "Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement", Transplantation, volume 59, 655-661, number 5, 1995).
Finally, it is known that viral diseases, in particular AIDS, make significant use of the infected cell's genetic material to replicate the virus. It has recently been discovered that the above-mentioned mycophenolic acid had the ability, given its inhibitory action on the formation of dGTP in cells, to block the activity of reverse transcriptase in vitro and thus to have an anti-HIV effect (V. Hiroshi Ichimura and J. A. Levy, "Polymerase substrate depletion: A novel strategy for inhibiting the replication of the human immunodeficiency virus", Virology 211, 554-560, 1995).
The object of the present invention is to provide a process for inhibiting deoxyribonucleotide triphosphate biosynthesis by animal, human or plant cells which does not exhibit the above-stated disadvantages, in particular unacceptable toxicity for healthy cells, and which thus prevents the large-scale and abnormal cellular production of deoxyribonucleic acid, which may result, for example, in cancerous cell proliferation.